Human cytomegalovirus (HCMV) is a complex human pathogen that causes disease in immune-compromised and immune naïve individuals. Our work focuses on understanding the molecular events by which HCMV takes control of the infected cell to facilitate virus replication. Our goal is to use this knowledge to define new targets for the development of novel antiviral drugs.
Our lab uses a combination of new technologies and traditional molecular virology techniques to investigate host:pathogen interactions between HCMV and the infected cell. Using these approaches we have discovered that HCMV employs a wide range of mechanisms to ensure that the environment of the infected cell is precisely modified to favor viral replication.
A major focus of our efforts is deciphering how HCMV alters cell signaling pathways to drive viral protein synthesis. One way by which HCMV promotes viral protein synthesis is by activating the cellular mTOR kinase, a key regulator of mRNA translation. We have found that HCMV employs a coordinated attack on cellular regulatory proteins that limit mTOR activity. For example, we have shown that the HCMV protein pUL38 binds and inhibits the mTOR antagonist TSC2. Ongoing work in the lab is focused on understanding how HCMV inhibits additional mTOR regulatory proteins, and the role of viral proteins in this process.
While mTOR plays an important role in the translation of most cellular mRNAs, we have found that its activity is not required for the translation of many viral mRNAs. Using mass spectrometry we have identified HCMV proteins that interact with the mRNA translation machinery during infection in the absence of mTOR activity. We are currently investigating the effect of these interactions on viral mRNA translation. We are also using new sequencing technologies to identify mRNAs whose translation is controlled by these viral proteins.
In contrast to its minimal role in mRNA translation, mTOR activation plays a major role in the remodeling of metabolism that occurs upon infection. We are in the process of defining the molecular events behind mTOR-dependent metabolic changes, and determining the role of specific metabolites affected by mTOR signaling in viral replication.
Spencer CM, Schafer XL, Moorman NJ, Munger J. Human Cytomegalovirus Induces the Activity and Expression of Acetyl-CoA Carboxylase, a Fatty Acid Biosynthetic Enzyme whose Inhibition Attenuates Viral Replication. J Virol. 2011 Apr 6. Epub ahead of print
Cristea IM, Moorman NJ, Terhune SS, Cuevas CD, O’Keefe ES, Rout MP, Chait BT, Shenk T. Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J Virol. 2010 Aug;84(15):7803-14
Paden CR, Forrest JC, Moorman NJ, Speck SH. Murine gammaherpesvirus 68 LANA is essential for virus reactivation from splenocytes but not long-term carriage of viral genome. J Virol. 2010 Jul;84(14):7214-24
Terhune SS, Moorman NJ, Cristea IM, Savaryn JP, Cuevas-Bennett C, Rout MP, Chait BT, Shenk T. Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA. PLoS Pathog. 2010 Jun 24;6(6)
Moorman NJ, Shenk T. Rapamycin-resistant mTORC1 kinase activity is required for herpesvirus replication. J Virol. 2010 May;84(10):5260-9
Moorman, NJ, Sharon-Friling, R, Shenk, T, Cristea, I. A targeted spatial-temporal proteomic approach implicates multiple cellular trafficking pathways in human cytomegalovirus virion maturation. Molecular and Cellular Proteomics. 2010 May;9(5):851-60
Pancheva D, Savaryn, JP Moorman, NJ, Shenk T, Terhune, SS. Human cytomegalovirus UL28 and UL29 open reading frames encode a spliced mRNA and stimulate accumulation of immediate-early RNAs. J Virol. 2009 Oct;83(19):10187-97
Moorman NJ, Cristea IM, Terhune SS, Rout MP, Chait BT, Shenk T. Human cytomegalovirus protein UL38 inhibits host cell stress responses by antagonizing the tuberous sclerosis protein complex. Cell Host Microbe. 2008 Apr 17;3(4):253-62
Terhune S.S., Torigoi E., Moorman N.J., Silva M., Qian Z., Shenk T., Yu D. Human cytomegalovirus protein UL38 blocks apoptosis. J Virol. 2007 Apr;81(7):3109-23
Evans, AG, Moorman, NJ, Willer DO, Speck S.H. The M4 gene of gammaHV68 encodes a secreted glycoprotein and is required for the efficient establishment of splenic latency. Virology 20;344(2):520- 31, 2006